Trial of Dasatinib Plus Ixabepilone in 2nd or 3rd Line Metastatic Breast Cancer

This study has been completed.
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Accelerated Community Oncology Research Network
ClinicalTrials.gov Identifier:
NCT00924352
First received: June 16, 2009
Last updated: October 11, 2013
Last verified: October 2013
  Purpose

The primary objective for the Phase I portion of the study is to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) and for the Phase II portion of the study is to evaluate progression free survival (PFS). Secondary objectives are response rate, clinical benefit rate, and overall toxicity.


Condition Intervention Phase
Metastatic Breast Cancer
Drug: Dasatinib
Drug: Ixabepilone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Dasatinib Plus Ixabepilone in 2nd or 3rd Line Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by Accelerated Community Oncology Research Network:

Primary Outcome Measures:
  • Phase I portion of the study: to determine the MTD and DLTs of the combination of dasatinib and ixabepilone [ Time Frame: 28 day cycle ] [ Designated as safety issue: Yes ]
  • Phase II portion of the study: to evaluate PFS of the combination of dasatinib and ixabepilone [ Time Frame: 28 day cycle ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Response rate of the combination of dasatinib and ixabepilone [ Time Frame: 28 day cycle ] [ Designated as safety issue: No ]
  • Clinical benefit rate of the combination of dasatinib and ixabepilone [ Time Frame: 28 day cycle ] [ Designated as safety issue: No ]
  • Overall toxicity of the combination of dasatinib and ixabepilone [ Time Frame: 28 day cycle ] [ Designated as safety issue: Yes ]

Enrollment: 56
Study Start Date: June 2009
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ixabepilone + Dasatinib

Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level − 1;12 mg/m2,Dose Level − 2;12 mg/m2.

Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level − 1;100 mg QD,Dose Level − 2;70 mg QD.

Drug: Dasatinib
Dasatinib tablets will be administered continuously starting on Day 1, Cycle 1 once daily (QD).Dose Level 2;140 mg QD,Dose Level 1;100 mg QD,Dose Level 0 (Starting Dose);100 mg QD,Dose Level − 1;100 mg QD,Dose Level − 2;70 mg QD.
Other Name: SPRYCEL
Drug: Ixabepilone
Ixabepilone, for injection 15 mg supplied with diluent for ixabepilone, 8 mL. Dose Level 2;20 mg/m2,Dose Level 1;20 mg/m2,Dose Level 0 (Starting Dose);16 mg/m2,Dose Level − 1;12 mg/m2,Dose Level − 2;12 mg/m2.
Other Name: IXEMPRA

Detailed Description:

In the Phase I portion of the study, patients will receive study treatment according to the assigned dose level. Ixabepilone will be administered over 1 hour on Days 1, 8, and 15 of a 28-day cycle. Dasatinib will be administered continuously starting on Day 1, Cycle 1 once daily (QD).

Three patients will be enrolled at dose level 0 and observed for dose-limiting toxicity (DLT) for 1 course of treatment.

Dose escalation or reduction will depend on the number of patients experiencing DLT as follows:

  • If 0 of 3 patients experiences a DLT, then 3 additional patients will be enrolled at the next higher dose level.
  • If 1 of 3 patients experiences a DLT, then 3 additional patients will be enrolled at that dose level.
  • If 2 of 3 or 3 of 3 patients experience a DLT, then 3 patients will be enrolled at the next lower dose unless 6 patients have already been treated at that dose.
  • If ≥2 of 6 patients experience a DLT at that dose level, then the MTD is considered to have been exceeded. At that point, 3 patients are treated at the next lower dose.
  • If no more than 1 of the 6 patients experiences a DLT, then the dose level will be escalated 1 level.

Maximum-tolerated dose (MTD) is defined as the dose at which ≤1 of 6 patients experience DLT, and above which ≥2 of 6 patients experience DLT.

In the Phase II portion of the study, dasatinib and ixabepilone will be administered at the MTD determined during Phase I. Dasatinib will be started on Day 1, Cycle 1 and will be administered continuously once daily. Ixabepilone will be administered over 1 hour on Days 1, 8, and 15 of a 28-day cycle. Patients will be treated with both agents for up to 8 cycles, after which stable or responding patients are eligible for monotherapy with dasatinib at the investigator's discretion in the absence of disease progression or unacceptable toxicity.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A patient must meet each of the following criteria to be considered eligible for inclusion in this study:

  1. Patient has the ability to understand and the willingness to sign a written informed consent including form according to institutional guidelines.
  2. Patient has histologically-proven breast cancer.
  3. Patient has locally recurrent or metastatic disease, measurable or non- measurable by RECIST criteria.
  4. Patient has HER2-negative disease or disease that is refractory to HER2- directed therapy.
  5. Patient is female or male ≥ 18 years of age.
  6. Patient has(ECOG)performance status of ≤ 2.
  7. Patient must have received at least 1 but no more than 2 prior chemotherapy regimens for locally recurrent or metastatic disease. Patients may have received neoadjuvant and/or adjuvant chemotherapy. These prior regimens can not have included ixabepilone or dasatinib. A line of chemotherapy will be defined as one or more agents used continuously or discontinuously (i.e., allowing a break or chemo holiday) without the addition of a new agent. Hormonal therapy will not be considered a line of therapy.
  8. Prior chemotherapy must have been completed at least 3 weeks prior to study treatment start (6 weeks for nitrosoureas and mitomycin), and the patient must have recovered from all associated toxicities (except for alopecia and neuropathy grade 1 according to CTCAE, v3.0 classification).
  9. Radiation therapy, immunotherapy, biologic therapy, and hormonal/endocrine therapy must have been completed at least 2 weeks prior to study treatment start. Any major surgery must have been completed at least 4 weeks prior to study treatment start.
  10. Patient has adequate organ, metabolic and bone marrow function as follows:

    1. Total bilirubin ≤ 1.0 × institutional ULN
    2. AST, ALT ≤ 2.5 × institutional ULN
    3. Serum sodium, potassium, calcium, magnesium, and phosphate ≥ institutional LLN. (Hypokalemia or hypomagnesemia must be corrected prior to dasatinib administration.)
    4. Serum creatinine < 1.5 × institutional ULN
    5. Hematologic function: - ANC ≥ 1500/mm3. -Platelet count ≥ 100,000/mm3. - Hemoglobin ≥ 10.0 g/dL
    6. PT and PTT < 1.5 x institutional ULN
  11. Ability to take oral medication (dasatinib must be swallowed whole).
  12. Concomitant medications:

    1. Patient agrees to discontinue St John's Wort at least 5 days prior to starting dasatinib therapy and while receiving dasatinib therapy.
    2. Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia.
    3. The use of CYP3A4 inducers, inhibitors, and substrates; medications that prolong QT interval; antacids; H2 blockers and proton pump inhibitors; and medications that inhibit platelet function and anticoagulation should be avoided during dasatinib therapy. These are restricted therapies that are permitted with caution when medically indicated.
  13. Women of childbearing potential must have a negative serum or urine pregnancy test prior to the start of study treatment.
  14. Patients of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 4 weeks after study treatment is stopped.

Exclusion Criteria:

A patient who meets any of the following criteria will be considered not eligible for inclusion in this study:

  1. Patient has had prior treatment with ixabepilone, dasatinib, or both.
  2. Patient has had more than 2 prior lines of chemotherapy for locally recurrent or metastatic breast cancer. A line of chemotherapy will be defined as one or more agents used continuously or discontinuously (i.e., allowing a break or chemo holiday) without the addition of a new agent. Hormonal therapy will not be considered a line of therapy.
  3. Patient has received a cumulative dose of > 360 mg/m2 of doxorubicin or > 600 mg/m2 of epirubicin.
  4. Prior radiation must not have included ≥ 30% of major bone marrow containing areas (pelvis, lumbar spine).
  5. Patients with CTC grade 2 or greater neuropathy (motor or sensory) at study entry.
  6. Patient has evidence CNS or brain metastases, unless CNS or brain metastases have been treated and stable for > 3 months.
  7. Patient has psychiatric illness or social situation that would limit or prohibit compliance with study requirements.
  8. Patient has an inability to take oral medication or inability to absorb oral medication.
  9. Patient has had any invasive cancer other than the one being treated in this study within 3 years with the exception of surgically cured nonmelanoma skin cancer; in situ carcinoma of the cervix; in situ carcinoma of the breast.
  10. Patient is receiving concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, or hormonal therapy for cancer).
  11. Patient has other serious medical conditions as judged by the Principal Investigator.
  12. Patient has a concurrent medical condition which may increase the risk of toxicity.
  13. Patient has a pleural or pericardial effusion of any grade.
  14. Patient has cardiac symptoms including any of the following:

    1. Uncontrolled angina, congestive heart failure or myocardial infarction within 6 months of study entry.
    2. Diagnosed congenital long QT syndrome.
    3. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
    4. Prolonged QTc on pre-entry ECG (> 450 msec).
    5. Hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.
  15. Patient has a history of significant bleeding disorder unrelated to cancer, including:

    1. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease).
    2. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).
    3. Ongoing or recent (≤ 3 months) significant GI bleeding.
  16. Patient is taking any of the following concomitant medications at study entry:

    a. Category I drugs that are generally accepted to have a risk of causing Torsades de pointes including (Patients must discontinue drug 7 days prior to starting dasatinib.):

    • quinidine, procainamide, disopyramide.
    • amiodarone, sotalol, ibutilide, dofetilide.
    • erythromycin, clarithromycin.
    • chlorpromazine,haloperidol,mesoridazine, thioridazine,pimozide .
    • cisapride,bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,halofantrine, levomethadyl, pentamidine,sparfloxacin, lidoflazine.
  17. Patient has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ixabepilone or dasatinib. Ixabepilone is contraindicated in patients who have a known, prior, severe (CTC grade 3 or 4) history of hypersensitivity reaction to a drug formulated in Cremophor® EL (polyoxyethylated castor oil).
  18. Patient has received any investigational agent or therapy within 30 days prior to study treatment start.
  19. Patient is unwilling or unable to comply with study requirements.
  20. Women who:

    1. are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study treatment, or
    2. have a positive pregnancy test at baseline, or
    3. are pregnant or breastfeeding.
  21. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00924352

Locations
United States, Connecticut
Hematology Oncology PC
Stamford, Connecticut, United States, 06902
United States, Georgia
Central Georgia Cancer Care
Macon, Georgia, United States, 31201
Northwest Georgia Oncology Centers
Marietta, Georgia, United States, 30060
United States, Illinois
North Shore Cancer Research
Skokie, Illinois, United States, 60076
United States, Iowa
Hematology Oncology Associates of the Quad Cities
Bettendorf, Iowa, United States, 52722
United States, Massachusetts
Baystate Medical Center
Springfield, Massachusetts, United States, 01107
United States, Montana
Hematology Oncology Centers of the Northern Rockies
Billings, Montana, United States, 59101
United States, New Jersey
Oncology Hematology Specialists, P.A.
Denville, New Jersey, United States, 07834
United States, North Carolina
The Moses H. Cone Regional Cancer Center
Greensboro, North Carolina, United States, 27403
United States, Ohio
North Coast Cancer Care
Sandusky, Ohio, United States, 44870
United States, Pennsylvania
Pennsylvania Oncology Hematology Associates
Philadelphia, Pennsylvania, United States, 19106
United States, Tennessee
The West Clinic
Memphis, Tennessee, United States, 38120
University of Tennessee Cancer Institute
Memphis, Tennessee, United States, 38104
Sponsors and Collaborators
Accelerated Community Oncology Research Network
Bristol-Myers Squibb
Investigators
Study Chair: Lee S. Schwartzberg, MD, FACP The West Clinic
  More Information

No publications provided

Responsible Party: Accelerated Community Oncology Research Network
ClinicalTrials.gov Identifier: NCT00924352     History of Changes
Other Study ID Numbers: ALSSMBC0804
Study First Received: June 16, 2009
Last Updated: October 11, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Accelerated Community Oncology Research Network:
Metastatic Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Epothilones
Dasatinib
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 16, 2014